PROJECT SUMMARY A major risk factor in the vulnerability to immune disorders is biological sex. In some of the most prevalent immune disorders such as allergy/anaphylaxis, autoimmune disease, and chronic pain disorders, females are at increased risk. Adult sex hormones, such as estrogen, may explain some of the sex differences; however, this is challenged by the fact that many immune disorders exhibit a sex bias in prepubertal children. Our recent published and preliminary studies have uncovered sex differences in the mast cell that may explain female vulnerability or male resilience to many immune disorders. Mast cells are innate immune cells that act as effector cells and orchestrators of the immune response. The fact that many mast cell-associated disorders (allergy, autoimmune disease, chronic pain disorders, irritable bowel syndrome) exhibit a sex bias in both childhood and adulthood positions the mast cell as a novel regulator of sex differences in immune diseases. Specifically, we have shown that female mast cells possess an increased capacity to synthesize, store and release potent mast cell mediators including histamine, serotonin, proteases, etc. In animal models of IgE- mediated anaphylaxis and psychological stress, female animals exhibited enhanced release of mast cell mediators and more severe pathophysiologic and clinical disease, similar to findings in humans. Moreover, our recent preliminary data demonstrates that sex differences in mast cells emerge early in life prior to puberty and thus may explain sex differences observed in children. The components of sexual differentiation that impact the mast cell phenotype and consequently increase female vulnerability to immune disorders is unknown. Based on preliminary data, we hypothesize that sex differences in mast cell phenotype and immune-related disease susceptibility are established early in life by perinatal androgens. In this F30 proposal, we aim to establish the role of perinatal androgens in determining sex differences in the mast cell and susceptibility/resiliency to later life immune pathophysiology in immunological and psychological stress models. Toward this goal, by conducting perinatal androgenization experiments in mice we will 1) identify the contribution of perinatal androgens in mast cell disease susceptibility and 2) determine the contribution of perinatal androgens in mast cell phenotype, function, and gene expression patterns. The exploratory studies proposed in the grant application will represent a major paradigm shift in the understanding of sex and mast cell-related immune disorders.